title: Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation.
abstract: OBJECTIVE
  Congenital long QT syndromes (LQTSs) are associated with prolonged ventricular repolarization and sudden cardiac death. Limitations to existing clinical therapeutic management strategies prompted us to develop a novel human in vitro drug-evaluation system for LQTS type 2 (LQT2) that will complement the existing in vitro and in vivo models.
  
  
  RESULTS
  Skin fibroblasts from a patient with a KCNH2 G1681A mutation (encodes I(Kr) potassium ion channel) were reprogrammed to human induced pluripotent stem cells (hiPSCs), which were subsequently differentiated to functional cardiomyocytes. Relative to controls (including the patient's mother), multi-electrode array and patch-clamp electrophysiology of LQT2-hiPSC cardiomyocytes showed prolonged field/action potential duration. When LQT2-hiPSC cardiomyocytes were exposed to E4031 (an I(Kr) blocker), arrhythmias developed and these presented as early after depolarizations (EADs) in the action potentials. In contrast to control cardiomyocytes, LQT2-hiPSC cardiomyocytes also developed EADs when challenged with the clinically used stressor, isoprenaline. This effect was reversed by β-blockers, propranolol, and nadolol, the latter being used for the patient's therapy. Treatment of cardiomyocytes with experimental potassium channel enhancers, nicorandil and PD118057, caused action potential shortening and in some cases could abolish EADs. Notably, combined treatment with isoprenaline (enhancers/isoprenaline) caused EADs, but this effect was reversed by nadolol.
  
  
  CONCLUSIONS
  Findings from this paper demonstrate that patient LQT2-hiPSC cardiomyocytes respond appropriately to clinically relevant pharmacology and will be a valuable human in vitro model for testing experimental drug combinations.
authors.affiliation: Wolfson Centre for Stem Cells, Tissue Engineering & Modelling, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Matsa
authors.forename: Divya
authors.initials: D
authors.lastname: Rajamohan
authors.forename: Emily
authors.initials: E
authors.lastname: Dick
authors.forename: Lorraine
authors.initials: L
authors.lastname: Young
authors.forename: Ian
authors.initials: I
authors.lastname: Mellor
authors.forename: Andrew
authors.initials: A
authors.lastname: Staniforth
authors.forename: Chris
authors.initials: C
authors.lastname: Denning
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics*
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020108:Nicorandil; D007545:Isoproterenol